ABSTRACT Administrative supplement in response to NOT-AG-18-008 AD/ADRD supplement program Parent Grant: R01 NS098769-01A1; The degradation of tau by selective autophagy PI: Gail VW Johnson The parent grant does not include disease-based models or studies; however the focus on the role of BAG3-mediated selective autophagy of tau during aging provides an excellent framework for delineating the contribution of this pathway to the pathogenesis of Alzheimer?s disease and Alzheimer?s disease related dementias (AD/ADRD). In this supplement we will use a P301S transgenic mouse model that expresses this mutant form of tau (with no N terminal inserts and 4 microtubule binding repeats; 0N4R) at ~5x endogenous tau levels (PS19 line) to extend the studies in the parent grant to test the hypothesis that BAG3 plays a pivotal role in facilitating the autophagic clearance of pathological tau species. These studies will be carried by using intrahippocampal injections of AAV2/9 Syn-shRNA-BAG3-CMV-mChe-PolyA (to knockdown BAG3), AAV2/9 Syn-rBAG3-CMV-mChe-PolyA (to overexpress BAG3) or AA2/9-CMV-mCherry (as a control). The same quantitative immunohistochemical measures, electron microscopy analyses and biochemical studies will be carried out as described in the parent grant. We also will determine how BAG3 modulates autophagy and the clearance of P301S in primary neurons following the framework and experimental design of aims 1.1 and 1.2 of the parent grant. Overall the studies in this administrative supplement will provide important insights into the processes governing autophagic clearance of P301S tau in general, and more specifically the role of BAG3 in this process. These data will provide the foundation for future studies into how BAG3 mediates the recognition of mutant forms of tau, and if the mechanisms differ for soluble and aggregated species. Further, the results from these studies will provide the basis for the development of interventions that may alleviate autophagic deficits caused by the presence of mutant forms of tau. Finally, as per the announcement for this funding mechanism, all the proposed work is within the scope of the parent grant, the work is focused on AD/ADRD and the work will stimulate additional activity leading to progress on AD/ADRD.